Clinical pharmacology of cardiac cyclic AMP in human heart failure: too much or too little?

Abstract

Introduction: Cyclic 3', 5'-adenosine monophosphate (cAMP) is a major signaling hub in cardiac physiology. Although cAMP signaling has been extensively studied in cardiac cells and animal models of heart failure (HF), not much is known about its actual amount present inside human failing or non-failing cardiomyocytes. Since many drugs used in HF work via cAMP, it is crucial to determine the status of its intracellular levels in failing vs. normal human hearts.

Areas covered: Only studies performed on explanted/excised cardiac tissues from patients were examined. Studies that contained no data from human hearts or no data on cAMP levels per se were excluded from this perspective's analysis.

Expert opinion: Currently, there is no consensus on the status of cAMP levels in human failing vs. non-failing hearts. Several studies on animal models may suggest maladaptive (e.g. pro-apoptotic) effects of cAMP on HF, advocating for cAMP lowering for therapy, but human studies almost universally indicate that myocardial cAMP levels are deficient in human failing hearts. It is the expert opinion of this perspective that intracellular cAMP levels are too low in human failing hearts, contributing to the disease. Strategies to increase (restore), not decrease, these levels should be pursued in human HF.

Keywords: Adenylyl cyclase; G protein-coupled receptor; cardiac function; cyclic AMP; heart failure; human heart; protein kinase a; signal transduction.

Figure 1.. Roles of cAMP in cardiac function.

Schematic illustration of the main effects of cAMP (via PKA) in cardiac inotropy, lusitropy, chronotropy, automaticity, and dromotropy. Not all pathways and effects are shown (e.g., Epac-mediated effects are omitted) for more clarity. Molecules or enzymes that are decreased in the failing human heart are shown in red fonts (AC activity, cAMP), while those that are increased in light blue fonts (Gai, PDE activity). Phosphorylation of MyBPC3 by PKA enhances both contraction and relaxation. A: Adenine; AC: Adenylyl cyclase; ATP: Adenosine triphosphate; cAMP: Cyclic 3`,5`-adenosine monophosphate; C: Catalytic subunit of PKA; cTnI: Cardiac troponin I; G: Guanine; Gai: Inhibitory G protein alpha subunit; HCN4: Hyperpolarization-activated Cyclic Nucleotide-gated (HCN)-4 cation channel; If: “Funny” (pacemaker) current; LTCC: L-type (voltage-gated) calcium channel; MyBPC3: Myosin-binding protein-C3 (cardiac); NCX: Na⁺/Ca²⁺-exchanger; NKA: Na⁺/K⁺-adenosine triphosphatase (sodium pump); P: Phosphorylation; PDE: Phosphodiesterase; PKA: Protein kinase A (cAMP-dependent protein kinase); PLM: Phospholemman; PLN: Phospholamban; R: Regulatory subunit of PKA; RyR2: Ryanodine receptor type 2 (cardiac); SERCA: Sarco(endo)plasmic reticulum calcium adenosine triphosphatase; SR: Sarcoplasmic reticulum. See text for details.